Microarray study reveals that HIV-1 induces rapid type-I interferon-dependent p53 mRNA up-regulation in human primary CD4+ T cells

<p>Abstract</p> <p>Background</p> <p>Infection with HIV-1 has been shown to alter expression of a large array of host cell genes. However, previous studies aimed at investigating the putative HIV-1-induced modulation of host gene expression have been mostly performed in established human cell lines. To better approximate natural conditions, we monitored gene expression changes in a cell population highly enriched in human primary CD4⁺T lymphocytes exposed to HIV-1 using commercial oligonucleotide microarrays from Affymetrix.</p> <p>Results</p> <p>We report here that HIV-1 influences expression of genes related to many important biological processes such as DNA repair, cellular cycle, RNA metabolism and apoptosis. Notably, expression of the p53 tumor suppressor and genes involved in p53 homeostasis such as GADD34 were up-regulated by HIV-1 at the mRNA level. This observation is distinct from the previously reported p53 phosphorylation and stabilization at the protein level, which precedes HIV-1-induced apoptosis. We present evidence that the HIV-1-mediated increase in p53 gene expression is associated with virus-mediated induction of type-I interferon (i.e. IFN-α and IFN-β).</p> <p>Conclusion</p> <p>These observations have important implications for our understanding of HIV-1 pathogenesis, particularly in respect to the virus-induced depletion of CD4⁺T cells.</p

Developmental associations between victimization and body mass index from 3 to 10 years in a population sample

In the current prospective study, we investigated (1) whether high and low BMI in early childhood puts a child at risk of victimization by their peers, and (2) whether being victimised increases BMI over the short- and long-term, independent of the effect of BMI on victimization. We also examined whether gender moderated these prospective associations. Participants were 1344 children who were assessed yearly from ages 3 -10 years as part of the Québec Longitudinal Study of Child Development (QLSCD). BMI predicted annual increases in victimization for girls aged 6 years and over; for boys aged 7 and 8 years of age, higher BMI reduced victimization over the school year. Further, victimization predicted annual increases in BMI for girls after age 6 years. When these short-term effects were held constant, victimization was also shown to have a three and five-year influence on annual BMI changes for girls from age 3 years. These short- and long-term cross-lagged effects were evident when the effects of family adversity were controlled. The findings support those from previous prospective research showing a link between higher BMI and victimization, but only for girls. Further, being victimised increased the likelihood that girls would put on weight over time, which then increased future victimization. The implications of these prospective findings for interventions are considered

TLR2 and TLR4 triggering exerts contrasting effects with regard to HIV-1 infection of human dendritic cells and subsequent virus transfer to CD4+ T cells

<p>Abstract</p> <p>Background</p> <p>Recognition of microbial products through Toll-like receptors (TLRs) initiates inflammatory responses orchestrated by innate immune cells such as dendritic cells (DCs). As these cells are patrolling mucosal surfaces, a portal of entry for various pathogens including human immunodeficiency virus type-1 (HIV-1), we investigated the impact of TLR stimulation on productive HIV-1 infection of DCs and viral spreading to CD4⁺T cells.</p> <p>Results</p> <p>We report here that engagement of TLR2 on DCs increases HIV-1 transmission toward CD4⁺T cells by primarily affecting <it>de novo </it>virus production by DCs. No noticeable and consistent effect was observed following engagement of TLR5, 7 and 9. Additional studies indicated that both HIV-1 infection of DCs and DC-mediated virus transmission to CD4⁺T cells were reduced upon TLR4 triggering due to secretion of type-I interferons.</p> <p>Conclusion</p> <p>It can thus be proposed that exposure of DCs to TLR2-binding bacterial constituents derived, for example, from pathogens causing sexually transmissible infections, might influence the process of DC-mediated viral dissemination, a phenomenon that might contribute to a more rapid disease progression.</p

Exon level transcriptomic profiling of HIV-1-infected CD4(+) T cells reveals virus-induced genes and host environment favorable for viral replication.

HIV-1 is extremely specialized since, even amongst CD4(+) T lymphocytes (its major natural reservoir in peripheral blood), the virus productively infects only a small proportion of cells under an activated state. As the percentage of HIV-1-infected cells is very low, most studies have so far failed to capture the precise transcriptomic profile at the whole-genome scale of cells highly susceptible to virus infection. Using Affymetrix Exon array technology and a reporter virus allowing the magnetic isolation of HIV-1-infected cells, we describe the host cell factors most favorable for virus establishment and replication along with an overview of virus-induced changes in host gene expression occurring exclusively in target cells productively infected with HIV-1. We also establish that within a population of activated CD4(+) T cells, HIV-1 has no detectable effect on the transcriptome of uninfected bystander cells at early time points following infection. The data gathered in this study provides unique insights into the biology of HIV-1-infected CD4(+) T cells and identifies genes thought to play a determinant role in the interplay between the virus and its host. Furthermore, it provides the first catalogue of alternative splicing events found in primary human CD4(+) T cells productively infected with HIV-1

Associations of Maternal Prenatal Smoking with Early Childhood Physical Aggression, Hyperactivity-Impulsivity, and Their Co-Occurrence

This study investigated associations between maternal prenatal smoking and physical aggression (PA), hyperactivity-impulsivity (HI) and co-occurring PA and HI between ages 17 and 42 months in a population sample of children born in Québec (Canada) in 1997/1998 (N=1745). Trajectory model estimation showed three distinct developmental patterns for PA and four for HI. Multinomial regression analyses showed that prenatal smoking significantly predicted children’s likelihood to follow different PA trajectories beyond the effects of other perinatal factors, parental psychopathology, family functioning and parenting, and socio-economic factors. However, prenatal smoking was not a significant predictor of HI in a model with the same control variables. Further multinomial regression analyses showed that, together with gender, presence of siblings and maternal hostile reactive parenting, prenatal smoking independently predicted co-occurring high PA and high HI compared to low levels of both behaviors, to high PA alone, and to high HI alone. These results show that maternal prenatal smoking predicts multiple behavior regulation problems in early childhood

Early risk factors for hyperactivity-impulsivity and inattention trajectories from age 17 months to 8 years.

CONTEXT: Attention-deficit/hyperactivity disorder is an etiologically heterogeneous neurodevelopmental condition with long-term negative outcomes. However, the early developmental course of hyperactivity-impulsivity and inattention symptoms and their association with previous environmental risk factors are still poorly understood OBJECTIVES: To describe the developmental trajectories of hyperactivity-impulsivity and inattention symptoms and to identify their prenatal, perinatal, and postnatal risk factors. DESIGN: Birth cohort from the general population. SETTING: Quebec Longitudinal Study of Child Development. PARTICIPANTS: The sample consisted of 2057 individuals, followed up from age 5 months to 8 years. MAIN OUTCOME MEASURES: Prenatal, perinatal, and postnatal risk factors assessed at age 5 months were considered predictors of group membership in high hyperactivity-impulsivity and inattention trajectories from age 17 months to 8 years. RESULTS: The frequency of hyperactivity-impulsivity symptoms tended to slightly decrease with age, whereas the frequency of inattention symptoms substantially increased up to age 6 years. However, trajectories of hyperactivity-impulsivity and inattention symptoms were significantly associated with each other. Risk factors for high trajectories of both types of symptoms were premature birth (adjusted odds ratio [aOR], 1.93; 95% CI, 1.07-3.50), low birth weight (2.11; 1.12-3.98), prenatal tobacco exposure (1.41; 1.03-1.93), nonintact family (1.85; 1.26-2.70), young maternal age at birth of the target child (1.78; 1.17-2.69), paternal history of antisocial behavior (1.78; 1.28-2.47), and maternal depression (1.35; 1.18-1.54). CONCLUSIONS: A large range of early risk factors, including prenatal, perinatal social, and parental psychopathology variables, act independently to heighten the likelihood of having persistently high levels of hyperactivity-impulsivity and inattention symptoms from infancy to middle childhood. Early interventions should be experimented with to provide effective tools for attention-deficit/hyperactivity disorder prevention

Extracellular ATP reduces HIV-1 transfer from immature dendritic cells to CD4+ T lymphocytes.

BACKGROUND: Dendritic cells (DCs) are considered as key mediators of the early events in human immunodeficiency virus type 1 (HIV-1) infection at mucosal sites. Previous studies have shown that surface-bound virions and/or internalized viruses found in endocytic vacuoles of DCs are efficiently transferred to CD4+ T cells. Extracellular adenosine triphosphate (ATP) either secreted or released from necrotic cells induces a distorted maturation of DCs, transiently increases their endocytic capacity and affects their migratory capacity. Knowing that high extracellular ATP concentrations are present in situations of tissue injury and inflammation, we investigated the effect of ATP on HIV-1 transmission from DCs to CD4+ T lymphocytes. RESULTS: In this study, we show that extracellular ATP reduces HIV-1 transfer from immature monocyte-derived DCs (iDCs) to autologous CD4+ T cells. This observed decrease in viral replication was related to a lower proportion of infected CD4+ T cells following transfer, and was seen with both X4- and R5-tropic isolates of HIV-1. Extracellular ATP had no effect on direct CD4+ T cell infection as well as on productive HIV-1 infection of iDCs. These observations indicate that extracellular ATP affects HIV-1 infection of CD4+ T cells in trans with no effect on de novo virus production by iDCs. Additional experiments suggest that extracellular ATP might modulate the trafficking pathway of internalized virions within iDCs leading to an increased lysosomal degradation, which could be partly responsible for the decreased HIV-1 transmission. CONCLUSION: These results suggest that extracellular ATP can act as a factor controlling HIV-1 propagation

Solvable Lie algebras with triangular nilradicals

All finite-dimensional indecomposable solvable Lie algebras $L(n,f)$, having the triangular algebra T(n) as their nilradical, are constructed. The number of nonnilpotent elements $f$ in $L(n,f)$ satisfies $1\leq f\leq n-1$ and the dimension of the Lie algebra is $\dim L(n,f)=f+{1/2}n(n-1)$

Identification of functional microRNAs released through asymmetrical processing of HIV-1 TAR element†

The interaction between human immunodeficiency virus type 1 (HIV-1) and RNA silencing pathways is complex and multifaceted. Essential for efficient viral transcription and supporting Tat-mediated transactivation of viral gene expression, the trans-activation responsive (TAR) element is a structured RNA located at the 5′ end of all transcripts derived from HIV-1. Here, we report that this element is a source of microRNAs (miRNAs) in cultured HIV-1-infected cell lines and in HIV-1-infected human CD4+ T lymphocytes. Using primer extension and ribonuclease (RNase) protection assays, we delineated both strands of the TAR miRNA duplex deriving from a model HIV-1 transcript, namely miR-TAR-5p and miR-TAR-3p. In vitro RNase assays indicate that the lack of a free 3′ extremity at the base of TAR may contribute to its low processing reactivity in vivo. Both miR-TAR-5p and miR-TAR-3p down-regulated TAR miRNA sensor activity in a process that required an integral miRNA-guided RNA silencing machinery. miR-TAR-3p exerted superior gene downregulatory effects, probably due to its preferential release from HIV-1 TAR RNA by the RNase III Dicer. Our study suggests that the TAR element of HIV-1 transcripts releases functionally competent miRNAs upon asymmetrical processing by Dicer, thereby providing novel insights into viral miRNA biogenesis